Biphenylene-substituted-butadienols

ABSTRACT

(2-biphenylenyl)-butadienols, e.g., 2-(2-biphenylenyl)-3,4pentadien-2-ol, and their preparation are described. The compounds are useful as anti-inflammatories.

United States Patent [19] Anderson BlPHENYLENE-SUBSTITUTED- BUTADIENOLS [75] Inventor: Paul L. Anderson, Dover, NJ.

[73] Assignee: Sandoz, Inc., E. Hanover, NJ.

[22] Filed: Dec. 28, 1973 [21] Appl. No.: 429,389

[52] U.S. Cl. 260/618 F; 260/239 B; 260/247.7 A; 260/268; 260/293.53; 260/326.87;

R; 260/543 R; 260/567.6 M; 260/618 D; 424/343 June 10, 1975 3,267,145 8/1966 Land at al 260/618 R FOREIGN PATENTS OR APPLICATIONS 2,258,349 9/1973 Germany 260/618 R OTHER PUBLICATIONS Gelin et al., Chemical Abstracts," Vol. 77, Abstract No. 113707u (1972).

Primary Examiner-Donald G. Daus Assistant Examiner-W. B. Springer Attorney, Agent, or Firm-Gerald D. Sharkin; Richard E. Vila; Frederick H. Weinfeldt [57] ABSTRACT (2-biphenylenyl)-butadien0ls, e.g., 2-(2- biphenylenyl)-3,4-pentadien-2-ol, and their preparation are described. The compounds are useful as antiinflammatories.

2 Claims, N0 Drawings BIPHENYLENE-SUBSTlTUTED-BUTADIENOLS This invention relates to biphenylene derivatives, and more particularly to (2-biphenylenyl)-butadienols, as well as to pharmaceutical compositions containing such compounds and to the pharmaceutical use of such compounds.

The compounds of this invention may be conveniently represented by the formula I:

\ CCH= C=CH wherein R is a hydrogen atom, methyl or ethyl, preferably methyl. Compounds I are obtainable by reducing with a complex metal hydride, a corresponding alkynol compound of the formula ll, (process a):

l II ACCECCH wherein R is as defined above; and A is L is either (a) a quaternary ammonium radical; (b) an ether selected from the group consisting of tetrahydrofuran-Z-yloxy; tetrahydropyran-Z-yloxyor 4-methoxy-tetrahydropyran-4-yloxy; (c) halo having an atomic. weight of from about 19 to 127, e.g., fluoro, chloro, bromo, or iodo; or (d) a sulfonyloxy radical.

The complex hydride reducing agents may be of the formula llla or lllb:

Z2 Z l Z Tl H IIIa, or '1 n III]:

wherein minum hydride, lithium diisobutylmethyl aluminum hydride, lithium trimethoxy aluminum hydride, diethyl aluminum hydride and diborane, preferably lithium aluminum hydride or sodium dihydrobis (2- methoxyethoxy) aluminate.

The complex hydrides (llla and lllb) are either known and may be prepared by methods described in the literature or where not known may be prepared by methods analogous to those for preparing the known compounds. Many of the complex hydrides are commercially available.

Process (21) should be carried out in a medium which is not detrimental to the reaction, such as in an aprotic organic solvent, e.g., an ether such as diethyl ether, tetrahydrofuran or dioxane, an aromatic medium, such as benzene, toluene or pyridine or a saturated aliphatic hydrocarbon, such as pentane, hexane or octane. The medium may be a mixture or a single material. The reaction may, for example, be carried out at about 40 to +l20C., e.g., at the boiling point of the medium. However, temperatures of from about l0 to +50C. are preferred. While the higher temperatures result in a faster reaction rate, reactions carried out at lower temperatures tend to give purer products. The reaction product (a Compound I) may be recovered by conventional means, e.g., by carefully adding a small amount of water or aqueous solution, e.g., aqueous ammonium chloride, or sodium hydroxide to the reaction mixture,

filtering off the inorganic by-products or hydrolysis products of the hydride ion source, and then separating the Compound I product from the organic phase by such means as precipitation, extraction, crystallization, chromatography or liquid-liquid extraction. As will be appreciated by those skilled in the art, it is preferred to exclude moisture from the reaction, e.g., by use of anhydrous solvents and conditions. The reaction may be advantageously carried out in an inert atmosphere, e.g., under nitrogen gas.

The compounds of formula II in which L is a quaternary ammonium radical are compounds of formula lla:

wherein A and R are as defined above; and L is the radical:

wherein R and R independently represent alkyl having 1 to 4 carbon atoms; unsubstituted cycloalkyl having 5 to 6 ring carbons, i.e., cyclopentyl or cyclohexyl; or together, with N, represent a heterocyclic ring having 5 to 7 members selected from the group consisting of unsubstituted pyrrolidino, piperidino, homopiperidino, morpholino, and their alkyl substituted derivatives containing from 1 to 3 alkyl groups of l to 4 carbon atoms;

R represents alkyl having 1 to 4 carbon atoms, e.g.,

' methyl, ethyl, propyl or butyl including isomeric forms where they exist, although the unbranched alkyls are preferred, especially methyl, and

X is an anion derived from a mineral acid or an organic sulfonic acid, provided that X is not fluoro, e.g., iodo or methylsulfonyl.

Compounds Ila can be prepared by quaternizing a compound of the formula V:

A, R, R and R are as defined above,

with a compound of the formula VI:

wherein A and R are as defined above, and L is tetrahydrofuran-Z-yloxy, tetrahydropyran-2- yloxy or 4-methoxy-tetrahydropyran-4-yloxy can be prepared by reacting a compound of the formula VII VII wherein A and R are defined above, with Grignard reagent formed by treating a compound of the formula VIII:

HC 5 C-CH L" vm wherein L" is as defined above, with ethyl, magnesium bromide in the conventional manner for carrying out Grignard reactions.

The compounds of formulae VII and VIII used in the production of compounds IIb are known or can be prepared from known compounds using conventional techniques.

The compounds of formula II in which L is halo other than iodo, i.e., those compounds of formula He:

IIc

wherein A and R are as defined above, and

L' is fluoro, chloro or bromo can be prepared by reacting a compound of the formula IX:

wherein A and R are as defined above with the appropriate halide selected from the group of thionyl chloride or bromide, phosphorus pentachloride or bromide and hydrocarbon sulfonyl fluorides, e.g., benzyl sulfonyl fluoride, tosyl fluoride and mesyl fluoride, in an organic medium such as hexane, benzene or dimethoxyglycol. For the chlorination and bromination a tertiary amine base, such as pyridine, is included in the reaction mixture and .the reaction temperature is about 0 to 20C. For the fluorination the reaction temperature is 0 to about C.

Compounds of formula II in which L is iodo are conveniently prepared by reacting corresponding compounds of formula He in which L is chloro, with sodium iodide in acetone, the reaction being carried out in conventional manner for replacing a chloro with an iodo.

The compounds of formula II in which L is a sulfonyloxy radical are compounds of formula IId:

IId

wherein A and R are as defined above, and

U" is a sulfonyloxy radical which may be either alkylsulfonyloxy in which the alkyl group may be substituted, e.g., halo, or unsubstituted and contain from 1 to as many as 16 or more, preferably I to 6 carbon atoms, e g., methane sulfonyloxy, ethanesulfonyloxy, 3- chloropropanesulfonyloxy, or 1- hexadecanesulfonyloxy; or arylsulfonyloxy in which the aryl group is phenyl, naphthyl or substituted phenyl, which may have from I to 3 substituents independently selected from the group consisting of alkyl of l to 6 car bon atoms, alkoxy of l to 6 carbon atoms, halo and nitro.

Compounds IId can be prepared by reacting a compound of the formula IX above with an appropriate alkylsulfonyl chloride, such as methanesulfonyl chloride, 3-chloropropanesulfonyl chloride or 1- hexadecanesulfonyl chloride or an arylsulfonyl chloride, such as benzensulfonyl chloride, 4- toluenesulfonyl chloride or 2-naphthalenesulfonyl wherein R and R are as defined above. This reaction may be carried out at temperatures of 0 to 50C., conveniently at room temperature, and in the presence of an organic solvent such as tetrahydrofuran. The compounds of formula Xl are known or can be produced in known manner by reacting a compound of the formula XIV:

wherein R and R are as defined above, with lithium metal at a temperature of 0 to 50C. in a suitable solvent such as ethylene diamine. The compounds of formula V can also be prepared by a process (b) which involves reacting a compound of formula XII:

XII

wherein A and R are as defined above, with a compound of formula XIII:

R1 HO- CIl N/ XIII wherein R and R are as defined above.

In process (b), a compound of formula XII is reacted with a compound of formula X!" at a temperature of to 50C. preferably at room tcmperaturv. in the presence of an inert solvent, and in he presence of mono-valent coinage metal ion, e.g., copper ion, as catalyst, preferably cuprous chloride or cuprous oxide, although salts and the like of other coinage metals, i.e., silver and gold (I), can likewise be used. The compounds of formula Xll can be prepared by reacting a compound of formula Vll above in a solvent such as dimethylacetamide or dimethylsulfoxide with a suitable acetylene reagent, such as sodium or lithium acetylide conveniently at room temperature.

The compounds of formulae XIII and XIV used in the above-identified preparations of compounds V are known or can be produced from known materials by conventional techniques, and many are commercially available.

The compounds of formula (I) are useful because they possess pharmacological activity in animals. In particular, the compounds (I) are useful as antiinflammatory agents as indicated by the Carrageenan induced edema test on rats (oral administration at l to 200 mg/kg), For such use, the compounds may be combined with a pharmaceutically acceptable carrier. and such other conventional adjuvants as may be necessary, and administered orally in such forms as tablets and capsules, elixirs, suspensions and the like or parenterally in the form of an injectable solution or suspension. The dosage administered will, of course, vary depending upon the compounds used and the mode of administration. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 1 milligram to about 250 milligrams per kilo gram, e.g., from about 1 milligram to about 175 milligrams per kilogram of body weight, preferably given in divided doses 2 to 4 times a day, or in sustained release form. For most mammals, the administration of from about milligrams to about 3,000 milligrams, e.g., from about milligrams to about 2,000 milligrams, of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprise from about 25 milligrams to about 1500 milligrams, e.g., from about 40 milligrams to about 11000 milligrams, of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

For the above usage, oral administration with carriers may take place in such conventional forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for manufacture or pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and tale. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period; Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preseratives (ethyl-phydroxybenzoate). Capsules preferably contain the active ingredient admixed with an inert diluent, e.g., calcium carbonate, calcium phosphate, Kaolin, polyethylfilled-capsules. as appropriate to the nature of the particular active ingredient.

' 8 aqueous phase is extracted once with 300 ml. of benzene. The combined organic phases are then washed with 500 ml. of 1N potassium hydroxide and then 300 ml. of saturated sodium chloride, respectively. dried over anhydrous magnesium sulfate. and evaporated to obtain crude tetrahydropyranyloxy-3-pentyne-2-ol which is chro- Representative formulations for administration. 2 to 4 times a day, in treating inflammation are liquid-filled. soft gelatin capsules prepared by conventional techniques and containing the following:

. I Weight lngredicnt in Milligrams 2 Z-biphenylenyl )-3 .4-pentadien-2-ol 50 170 peanut Ol' 80581116 Oll 1n the following example which is illustrative of the invention, temperatures are in degrees centigrade, and room temperature is to 30C., unless indicated oth- Step ATo a Grignard mixture prepared in conventional manner from 8.4 g. of magnesium (etched in {chloroform and iodine) and 41 g. of ethyl bromide in a total of 200 ml. of dry tetrahydrofuran, there is dropwise added a solution of 47.6 g. of 3-(2'-tetrahydropyranyloxy)-propyne in 75 ml. of dry tetrahydrofuran. After 1.5 hours at room temperature a solution of 19.4 g. of 2-acetyl biphenylene in 100 ml. of dry tetrahydrofuran is dropwise added. After remaining for 18 hours at the reaction mixture is poured into 600 ml. of saturated ammonium chloride solution. The

matographed over silica gel.

Step B--Under a nitrogen atmosphere. with ice-bath cooling to a solution of 1 1.4 g. of the product of Step A. in ml. of dry tetrahydrofuran, there is added. dropwise', 30 ml. of lithium aluminum hydride in ether 1.1 molar). The mixture is stirred for 2 hours with ice bath cooling and then allowed to stand for 18 hours at 25, 10 ml. of aq. potassium hydroxide is carefully added followed by 10 g. of sodium sulfate and 2 g. of magnesium sulfate. The mixture is filtered and then evaporated to obtain a crude oil which is purified by chromatographic separation and silica gel preparative plate to give refined 2-(Z-biphenylenyl)-3,4-pentadien- 2-ol.

Repeating the procedure of this example but using in place of the Z-acetyl-biphenylene used in Step (A), an approximately equivalent amount of:

a. 1-(2-biphenylenyl)-propan-1-one; or

b. 2-biphenylenecarboxaldehyde; there is similarly obtained:

a. Z-(Z-biphenylenyl)-4,5-hexadien-3-ol; or

b. l-('2-biphenylenyl)2,3-butadien- 1 -ol.

'What is claimed is:

l. A compound of the formula: 

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 which is 2-(2-biphenylenyl)-3,4-pentadien-2-ol. 